Every year, over 1.5 million individuals in the US are diagnosed with cancer. Cachexia, defined as an involuntary weight loss >5%, is present in up to 80% of these patients and is the result of an imbalance between food intake and energy expenditure (EE). Cachexia contributes to a decrease in functional performance, quality of life and survival. However, treatments for this condition are lacking. In non-cancer models, administration of the hormone ghrelin or its mimetics (GHS) increases energy intake and decreases energy expenditure. This leads to an increase in lean body mass (LBM) and fat mass. However, their role in cancer cachexia has not been established. The long-term objective of this research is to determine the extent to which ghrelin mimetics will affect energy intake and energy expenditure, and the effect that these changes will have on body weight, body composition, protein accretion and functional performance in cancer patients with cachexia. Our hypotheses are that, in the setting of cancer-induced cachexia and compared to placebo, ghrelin mimetics (GHS) will: a) increase appetite and food intake, b) increase body weight, LBM and protein mass, and prevent fat loss, c) decrease resting EE and d) increase muscle strength and functional performance. The specific aims are to establish in veterans with cancer-induced cachexia the effects of GHS on: 1) appetite and food intake, 2) body weight and body composition, 3) resting energy expenditure and 4) functional performance. In addition, we have an exploratory aim of establishing the effect of GHS on circulating TNF-1 and IL-6 levels in this setting. The hypothesis is that GHS will decrease these markers. Research Design and Methods: In this double-blind, placebo-controlled trial, 90 subjects with non-small cell lung cancer and cachexia will be randomized to: 1) placebo or 2) GHS for 12 weeks. Safety and efficacy will be assessed at 4, 8 and 12 weeks and comparisons will be made for changes from baseline between groups. Appetite will be assessed by a visual analogue scale and food intake by a food diary. Lean body mass will be assessed by total body potassium measurement; protein content by prompt 3-activation system and fat mass by DEXA. Resting energy expenditure will be measured by indirect calorimetry. Functional performance will be assessed by questionnaires and by measuring changes in muscle strength, physical activity levels, stair climbing power and the 6-minute walk test. IL-6 and TNF-1 will be measured by ELISA. Relevance to the VA Mission: The present proposal will improve our understanding of symptoms that affect cancer patients. Collectively, these outcomes will establish the role of ghrelin mimetics in cancer cachexia and give us an insight into their mechanisms of action. This will improve quality of life and may open new avenues for the treatment of these symptoms. An improvement in functional performance is expected to allow patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. PUBLIC HEALTH RELEVANCE: Cancer and its complications including cachexia (involuntary weight loss) and anorexia (poor appetite) are very common problems in our veterans. We propose to test the effects of a novel agent called anamorelin on veterans with cancer cachexia and anorexia. This proposal will have a direct impact on their quality of life and will open new avenues for the treatment of these symptoms for which there are no effective treatments at this point. An improvement in these symptoms also will allow patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. Other conditions associated with cachexia such as heart failure or chronic lung disease are very common in our veterans and may benefit from the knowledge that this proposal will bring because the results generated by the proposed experiments will set the bases for future trials in these conditions.